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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 1906-1910
Copyright © 1998 by The Endocrine Society

Original Studies

Risedronate, a Highly Effective Oral Agent in the Treatment of Patients with Severe Paget’s Disease1

Frederick R. Singer, Thomas L. Clemens, Rachelle A. Eusebio and Pirow J. Bekker

John Wayne Cancer Institute (F.R.S.), Santa Monica, California 90404; University of Cincinnati School of Medicine (T.L.C.), Cincinnati, Ohio 45267; and Procter and Gamble Pharmaceuticals (R.A.E., P.J.B.), Cincinnati, Ohio 45242


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Thirteen patients with severe Paget’s disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SINCE the introduction of bisphosphonates as agents in the treatment of Paget’s disease of bone in 1971 (1), these agents have become the therapies of choice in the treatment of most patients with this disease. This has come about for several reasons. These agents are highly effective in inhibiting osteoclastic bone resorption, the process that is generally believed to be the primary abnormality in Paget’s disease (2). The bisphosphonates also are generally well tolerated and seldom produce any toxic responses (3). Although many patients have benefited from bisphosphonate treatment, patients with the most extensive and metabolically active disease often fail to respond optimally to the less potent bisphosphonates (4, 5) or to other agents (6, 7).

Risedronate is a highly potent bisphosphonate with a pyridinyl side-chain. Although it has low oral bioavailability (8), its high potency makes it a promising treatment for a variety of bone diseases in which excessive osteoclastic bone resorption is an important component. This study was conducted in a group of patients with very severe Paget’s disease of bone who were poorly responsive to other available treatment modalities. The results indicate that oral risedronate (30 mg daily for 8 weeks) is highly effective and generally well tolerated in the treatment of such patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

This was an open label, single center, oral dose study. All patients were to receive 30 mg oral risedronate daily for 8 weeks. Patients were then to be followed for 16 weeks without further treatment (total period, ~6 months). Patients who did not fully respond [normalization of serum alkaline phosphatase (SAP) activity] or who relapsed (SAP increased above upper limit of reference range after normalization) qualified for a second treatment period of 8 weeks with 30 mg risedronate. These patients were again followed for another 16 weeks without treatment.

Patients

Male and postmenopausal female patients, 18–80 yr of age with severe Paget’s disease (SAP at least 9 times the upper limit of normal) documented by x-rays, were eligible for the study. Patients with one or more of the following criteria were excluded from the study: weight not within ±25% of the desirable values for height and body frame as given in standard weight tables; a history of an allergic reaction to bisphosphonates; chronic alcohol or drug abuse, evidence of significant psychiatric or organic disease (other than Paget’s disease); clinically significant abnormal laboratory values other than those associated with Paget’s disease; previous treatment of Paget’s disease with bisphosphonates (within 6 months), mithramycin (within 3 months), or calcitonin (within 1 month); imminent risk of bone fracture or sarcomatous Pagetic bone transformation; neurological or cardiac complications of Paget’s disease; or serum FSH and estradiol levels compatible with premenopause. All patients gave written informed consent before entering the study. The study was approved by the institutional review committee of Cedars-Sinai Medical Center.

Dose form and dosing instructions

Patients received three 10-mg gelatin capsules containing risedronate sodium daily. These capsules were supplied by Procter and Gamble Pharmaceuticals. Excipients included microcrystalline cellulose, hydrous lactose, and magnesium stearate. Patients were instructed to take the risedronate capsules with 4 oz. (120 mL) water, 2 h away before or after any meal, as food may interfere with intestinal absorption. Patients were instructed not to take dairy products or antacids containing calcium, iron, magnesium, or aluminum within 2 h of treatment. No instructions were provided regarding staying upright after taking risedronate.

Biochemical evaluation

Fasting blood and 2-h urine collections were obtained at baseline and at weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, and 48.

A complete blood count and biochemical panel, including calcium, phosphorus, SAP, other liver enzymes, and renal function tests, were evaluated at each visit. Serum intact PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] were measured in each specimen by previously described methods (9). Urinary hydroxyproline (10)/creatinine and urinary calcium/creatinine ratios were determined in each urine specimen.

The primary determinant for effectiveness was the SAP response. This was expressed as the percent change in SAP from the baseline.

Safety measures

Adverse events reported by patients or observed by the investigators were recorded at all visits. Physical examinations, hematology, serum chemistries, and urinalysis were assessed throughout the study.

Statistical analysis

SAP was the primary parameter of interest. The significance of the percent change from baseline was assessed at each visit during the first treatment period and retreatment period by t test or signed rank test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Biochemical response

Thirteen patients were enrolled. Baseline characteristics are summarized in Table 1Go. All patients had severe Paget’s disease, with a mean baseline SAP level (1792.5 IU/L) 17 times the upper limit of the normal reference range (108 IU/L). All patients had previously received treatment for Paget’s disease. These data are listed in Table 2Go. Five of the patients had received three consecutive 30-mg infusions of pamidronate. In four, the serum alkaline phosphatase activity did not decrease by more than 50%, and in one, it decreased 64%, but the final level was 1425 IU/L.


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  		Table 1. Baseline characteristics of the study population

 

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  		Table 2. Baseline characteristics and prior therapies for Paget’s disease

 
In Fig. 1AGo, the percent change from baseline in SAP is shown for all patients (intent to treat population). In Fig. 1BGo, individual patient data are shown. In Table 3Go, the SAP data are summarized. Risedronate (30 mg for 8 weeks) produced a mean decrease from baseline in SAP of 77% by week 24 (~6 months). Upon retreatment, which was given to 10 patients, there was a further statistically significant decline in SAP to a final mean percent decrease of 87% from the original baseline. The mean SAP level decreased from 1792.5 IU/L at baseline to 192.9 IU/L by week 24 of the retreatment period. All patients who completed the study had at least a 77% decrease in SAP. One patient was within the normal range by the end of the retreatment period. One patient had a 28% decrease from baseline in SAP, but received only partial treatment because of early withdrawal due to an adverse event deemed unrelated to risedronate. Another patient had an increase from baseline in SAP; this patient had not taken risedronate daily and subsequently withdrew from the study due to diarrhea and dizziness.



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  		Figure 1. A, Percent change from baseline in SAP in patients receiving 30 mg oral risedronate daily for 8 weeks. Data are shown as means, with error bars representing the SEMs. B, SAP data over time for individual patients. Solid lines indicate patients who had received prior pamidronate treatment.

 

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  		Table 3. Summary of serum alkaline phosphatase data over time

 
The urinary hydroxyproline/creatinine and calcium/creatinine data are shown in Fig. 2Go. The maximum mean percent decrease from baseline in hydroxyproline excretion during the initial treatment period was 64%, and this decreased further to 79% during the retreatment period. A rapid onset of inhibition of bone resorption was observed, with a statistically significant mean decrease from baseline observed at week 2. As has been noted in previous studies of bisphosphonate therapy, hydroxyproline excretion decreased significantly before a major decrease in SAP. For example, by week 2, there was a mean percent decrease of 22% in hydroxyproline excretion, whereas the mean decrease in SAP was 8%. There was also a decrease in mean urinary calcium/creatinine levels during treatment and retreatment.



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  		Figure 2. Urinary hydroxyproline/creatinine (solid lines) and calcium/creatinine (dashed lines) data over time. Data presented are means, with error bars representing the SEMs.

 
The mean serum calcium and phosphorus data are shown in Fig. 3Go. There were statistically significant changes from baseline in mean serum calcium during treatment and retreatment periods. The decrements were small and transient, and the mean level returned to approximately the baseline level by the end of the follow-up periods. No patient developed clinical symptoms of hypocalcemia. The mean serum phosphorus changes followed the same pattern as that observed for serum calcium. Serum PTH and 1,25-(OH)2D data are displayed in Fig. 4Go. There were mean increases in serum PTH and 1,25-(OH)2D during the treatment and retreatment periods. Mean levels returned to near-baseline levels, however, by the end of the follow-up periods. Serum 25-hydroxyvitamin D levels were within the normal range and remained relatively unchanged over the course of the study (data not shown).



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  		Figure 3. Serum calcium (solid lines) and phosphorus (dashed lines) data over time. Data presented are means, with error bars representing the SEMs.

 


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  		Figure 4. Serum intact PTH (solid lines) and 1,25-(OH)2D (dashed lines) data over time. Data presented are means, with error bars representing the SEMs.

 
Safety and tolerability

Three patients withdrew from the study due to adverse events: one due to a transient ischemic event; one due to substernal chest pain, dyspepsia, and abdominal pain; and a third due to dizziness and diarrhea. The investigators considered the transient ischemic event to be doubtfully related to risedronate treatment. Esophageal and gastric endoscopy performed on the patient with substernal chest pain was normal. One patient had a burn accident, fell, and fractured her hip. She had surgical repair and completed the study. Two other patients were withdrawn during the study: one due to a protocol violation and another voluntarily.

There were no clinically meaningful laboratory changes over the course of the study other than those that reflected inhibition of bone resorption and bone formation. These were expected based on the pharmacology of risedronate.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study clearly demonstrates that a low oral dose of 30 mg risedronate given daily for only 8 weeks is highly effective in inducing a rapid reduction in biochemical markers of disease activity in patients with severe, otherwise poorly responsive, Paget’s disease of bone. Retreatment produced further reductions in biochemical markers, which indicates further benefit from a second course of 30 mg daily for 8 weeks. These results suggest that risedronate therapy could be successfully applied in patients who respond inadequately to therapies such as calcitonin, etidronate, and even pamidronate.

All patients who completed two courses of risedronate treatment (16 weeks) had at least a 77% decrease in SAP from the baseline. Patients in this study had a mean SAP value 17 times the upper limit of normal. In two other studies in which patients received 40 mg alendronate daily for 6 months, 78–88% of the patients showed at least a 60% decrease from baseline in SAP (11, 12); the mean baseline SAP values were approximately 7 and 5 times the upper limit of the reference range in these two studies, respectively. In a study in which patients received 400 mg tiludronate daily for 3 or 6 months, 60% and 70% of the patients showed at least a 50% decrease in SAP from the baseline, respectively (5); the mean baseline SAP value was approximately 5 times the upper limit of the reference range in both treatment groups. In another study (13) in which patients took 400 mg tiludronate daily for 6 months, 25% of the patients had at least a 50% decrease in SAP from the baseline; the mean baseline SAP value was approximately 3 times the upper limit of the reference range.

Generally, the oral treatment period with different bisphosphonates is 3–6 months (13, 14, 15, 16, 17, 18, 19, 20); the recommended treatment period for tiludronate is 3 months (5). In this study, a treatment period of only 8 weeks of oral risedronate was very effective in reducing the biochemical markers of disease activity. The reason for the greater efficacy of risedronate compared to that of the other bisphosphonates is probably its greater antiresorptive potency (22). In an earlier study in which oral doses of 10, 20, and 30 mg risedronate were given for 1 month, 30 mg was identified as the optimal dose (23). Continuous treatment with 20 or 30 mg risedronate for longer than 2 months did not provide additional benefit (24).

Risedronate was given 2 h before or after any meal. This led to an excellent pharmacological response and is therefore a viable alternative to early morning treatment in a fasted state (25). Alendronate must be given early in the morning on an empty stomach with a full glass of water, because oral bioavailability is negligible when it is given 2 h after meals (26). Patients taking alendronate must also remain upright until they have breakfast in an attempt to minimize esophageal irritation, an adverse reaction that can produce considerable morbidity (27, 28, 29, 30, 31, 32). Another aminobisphosphonate, pamidronate, has been mainly used iv, as oral pamidronate has the potential to cause gastrointestinal irritation (33).

Inhibition of bone resorption by risedronate led to slight decreases in serum calcium and serum phosphorus. Homeostatic mechanisms restored the serum calcium levels by an increase in serum PTH and 1,25-(OH)2D. Increased renal tubular reabsorption of calcium and increased intestinal calcium absorption were probably responsible for returning serum calcium to baseline levels. Serum phosphorus was also restored to baseline levels. With etidronate treatment, increases in serum phosphorus are sometimes observed during treatment. This is thought to be due to increased renal tubular reabsorption of phosphate (34, 35). In this study with risedronate, serum phosphorus levels were never noted to rise. In part this could be due to the increase in PTH secretion. Also, differences in the mechanism of action of the bisphosphonates could play a role. David and colleagues, for example, recently reported that another bisphosphonate, tiludronate, inhibits the vacuolar proton pump of the osteoclast, whereas alendronate was less effective (36). This may be relevant, as the renal tubular vacuolar proton pump is very similar to the osteoclast proton pump (37, 38).

Even though the changes in serum calcium in patients treated with risedronate were minor and not of clinical consequence, it is recommended that patients have an ample intake of calcium during treatment (but at a time different from risedronate intake) to minimize the hypocalcemic treatment effect.

In our extensive experience with the treatment of Paget’s disease, the suppression of biochemical activity noted in these severely affected patients was remarkable, particularly considering the relatively short duration of oral treatment. The most impressive response was in a woman with a baseline SAP of 5090 IU/L (47 times the upper limit of normal.) Her SAP was 163 IU/L at month 40 and 242 IU/L at the end of the study.


   Acknowledgments
 
The authors thank A. Valentin-Opran, M.D., Ph.D., for his contribution to the successful completion of this study.


   Footnotes
 
Address all correspondence and requests for reprints to: Dr. Frederick R. Singer, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, California 90404.

1 This work was supported by funds provided by Proctor and Gamble Pharmaceuticals. Back

Received August 27, 1997.

Revised February 18, 1998.

Accepted February 25, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Smith R, Russell RGG, Bishop M. 1971 Diphosphonates and Paget’s disease of bone. Lancet. 1:945–947.[Medline]
  2. Schmorl G. 1932 Über Ostitis deformans Paget. Virchows Arch Pathol Anat Physiol. 283:694–751.[CrossRef]
  3. Singer FR, Minoofar P. 1995 Bisphosphonates in the treatment of disorders of mineral metabolism. Adv Endocrinol Metab. 6:259–288.[Medline]
  4. Meunier PJ, Ravault A. 1991 Treatment of Paget’s disease with etidronate disodium. In: Singer FR, Wallach S, eds. Paget’s disease of bone. Clinical assessment, present and future therapy. New York: Elsevier; 86–99.
  5. Roux C, Gennari C, Farrerons J, et al. 1995 Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget’s disease of bone. Arthritis Rheum. 38:851–858.[Medline]
  6. Singer FR, Fredericks RS, Minkin C. 1980 Salmon calcitonin therapy for Paget’s disease of bone. The problem of acquired clinical resistance. Arthritis Rheum. 23:1148–1154.[Medline]
  7. Ryan WG, Schwartz TB, Perlia CP. 1969 Effects of mithramycin on Paget’s disease of bone. Ann Intern Med. 70:549–557.
  8. Mitchell DY, Eusebio RA, Heise MA, et al. 1996 The effect of dosing regimen on the pharmacokinetics of risedronate administered to healthy subjects. J Bone Miner Res. 11(Suppl 1):M661.
  9. Meier DE, Luckey MM, Wallenstein S, Clemens TL, Orwoll ES, Waslein CI. 1991 Calcium, vitamin D, and parathyroid hormone status in young white and black women: association with racial differences in bone mass. J Clin Endocrinol Metab. 72:703–710.[Abstract/Free Full Text]
  10. Blumenkrantz N, Asboe-Hanson G. 1973 A quick and specific assay for hydroxyproline. Anal Biochem. 55:288–291.[CrossRef][Medline]
  11. Siris E, Weinstein RS, Altman R, et al. 1996 Comparative study of alendronate vs. etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab. 81:961–967.[Abstract]
  12. Reid IR, Nicholson GC, Weinstein RS, et al. 1996 Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med. 101:341–348.[CrossRef][Medline]
  13. Reginster JY, Jeugmans-Huynen AM, Albert A, et al. 1988 Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate, in the treatment of Paget’s disease of bone. Bone. 9:349–354.[Medline]
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  17. Delmas PD, Chapuy MC, Vignon E, et al. 1982 Long term effects of dichloromethylene diphosphonate in Paget’s disease of bone. J Clin Endocrinol Metab. 54:837–844.[Abstract/Free Full Text]
  18. Meunier PJ, Chapuy MC, Alexandre C, et al. 1980 Effects of disodium dichloromethylene diphosphonate (Cl2 MDP) on Paget’s disease of bone. Adv Exp Med Biol. 128:299–309.[Medline]
  19. Frijlink WB, Bijvoet OLM, Te Velde J, Heynen G. 1979 Treatment of Paget’s disease with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). Lancet. 1:799–803.[Medline]
  20. Fraser TRC, Ibbertson HF, Holdaway IM, et al. 1984 Effective oral treatment of severe Paget’s disease of bone with APD (3-amino-1-hydroxypropylidene-1, 1-bisphosphonate): a comparison with combined calcitonin + EHDP (1-hydroxyethylidene-1, 1-bisphosphonate). Aust NZ J Med. 14:811–818.
  21. Deleted in proof.
  22. Geddes AD, D’Souza SM, Ebetino FH, Ibbotson KJ. 1994 Bisphosphonates: structure-activity relationships and therapeutic implications. In: Heersche JNM, Kanis JA, eds. Bone and mineral research. Amsterdam: Elsevier; 265–306.
  23. Brown JP, Johnston Jr CC, Reginster J-Y, Ryan WG, Ste-Marie L-G, Bekker PJ. Dose response of risedronate for Paget’s disease. Proc of the 79th Meeting of The Endocrine Society. 1997; 488.
  24. Boyle I, Brown J, Davies J, et al. 1992 Risedronate: preliminary results on dose dependency of cumulative doses of a bisphosphonate in pagetic patients. J Bone Miner Res. 7:S299.
  25. Mitchell DY, Eusebio RA, Heise MA, et al. 1996 The effect of dosing regimen on the pharmacokinetics of risedronate administered to healthy subjects. J Bone Miner Res. 11(Suppl 1):M661.
  26. Gertz BJ, Holland SD, Kline WF, et al. 1995 Studies of the oral bioavailability of alendronate. Clin Pharmacol Ther. 53:288–298.
  27. De Groen PC, Lubbe DF, Hirsch LJ, et al. 1996 Esophagitis associated with the use of alendronate. N Engl J Med. 335:1016–1020.[Abstract/Free Full Text]
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  36. David P, Nguyen H, Barbier A, Baron R. 1996 The bisphosphonate tiludronate is a potent inhibitor of the osteoclast vacuolar H+-ATPase. J Bone Miner Res. 11:1498–1507.[Medline]
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